In vivo delivery of heat shock protein 70 accelerates wound healing by up‐regulating macrophage‐mediated phagocytosis

Injury causes tissue breakdown, which releases large quantities of intracellular contents into the extracellular space. Some of these materials are well-established activators of the immune system and include heat shock proteins (HSPs), uric acid, nucleotides, High Mobility Group Box-1 protein (HMGB-1), and DNA. Here, we show that in vivo delivery of HSPs into BALB/cJ mice with full-thickness wounds accelerates the rate of wound closure by 60% as compared with control-treated mice. The onset is rapid and the effect is sustained, dose dependent, and protein specific. Adoptive transfer of RAW264 macrophages pretreated with HSP70 into naïve recipients with a wound transfers the HSP-mediated effect on the rate of wound closure. Further, we demonstrate that part of the mechanism by which HSP70 accelerates wound closure is through the stimulation of macrophage-mediated phagocytosis of wound debris. Disabling the HSP70-mediated enhancement of phagocytosis abrogates the HSP-mediated acceleration of the healing process. These findings create two opportunities: one, therapeutic, wherein HSP70 could be used in the clinical management of wounds; and two, pathophysiologic, to decode signals by which the host defenses recognize and respond to injury.